Atopic dermatitis (AD) is a common allergic disease seen in 10-20% of infants. While severity often diminishes with age, AD can persist throughout life. Moreover, AD severity can be a predictor of subsequent allergic disease as 60% of children who have AD will develop other atopic diseases, including asthma. Thus, it is often thought that AD is the first step on the "Allergic March" towards more severe atopic disease. While both defects in skin and a predisposition towards a hyper-Th2 response contribute towards AD, it is not clear which is the primary defect in the pathogenesis of AD. Chronic lesions convert to inflammation more characteristic of Th1-mediated immunity though what triggers this switch is unclear. In this AADCRC application, we will define several of the factors that contribute to disease initiation and exacerbation. In Project 1, patient samples and a mouse model of AD resulting from hyper-Th2 responses will be used to determine which cytokine and signaling pathways correlate with, or are required for, AD development. The mouse model of AD will also be used to define the effects of AD concurrent with the development of other atopic diseases. Project 2 will examine the contribution of dendritic cells as mediators of innate immunity in the development of AD by examining the function of DC populations in patient samples and mice that have AD and their ability to direct either Th2 or Th1 dependent immunity. Project 3 will qualitatively and quantitatively define bacteria and bacterial products from infected AD lesions. The role of the lipid mediator platelet-activating factor (PAF) and toll-like receptors in bacterial product-mediated inflammation and immunomodulation will be assessed both in vitro as well as in vivo using cellular and murine models. These three projects, supported by an Administrative and Resources Cores, are highly interactive and interrelated. The focus of this application, coupled with the complementary backgrounds of each of the Project Directors, provide a scientific environment poised to make rapid progress in defining the roles of immune components in Atopic Dermatitis. Lay summary-Atopic dermatitis is a very common allergic disorder affecting 10-20% of infants. While it is not a life-threatening disease, it is a source of great discomfort and can have adverse effects on social and emotional development. Additionally, it is a strong indication for the development of other allergic diseases later in life, including asthma. This proposal examines the development of atopic dermatitis and how development may impact other allergic diseases.